Triazole derivative or salt thereof, preparation process thereof and pharmaceutical containing said compound as an effective ingredient

ABSTRACT

Described is a triazole derivative represented by the formula (1):                    
     wherein R 1  represents a hydrogen atom, a lower alkyl group or an aralkyl group, X 1  and X 2  are the same or different and each independently represents a hydrogen atom, a halogen atom or a halogenoalkyl and n stands for an integer of 0 to 2, or salt thereof; a preparation process of said compound and a pharmaceutical comprising said compound as an effective ingredient. 
     The compound as described above has high antimycotic activity and is useful for the prevention and treatment of mammalian mycotic infections.

This application is a Division of application Ser. No. 09/207,924 filedon Dec. 9, 1998, which is now U.S. Pat. No. 6,083,968.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a triazole derivative or salt thereof whichhas excellent antimycotic action and high safety, an intermediate forpreparing said compound and a pharmaceutical comprising said compound asan effective ingredient.

2. Description of the Related Art

Mycosis can be classified into two types, that is, superficial mycosisrepresented by various trichophytosis, marginated eczema, psoriasis,cutaneous candidiasis or the like and deep seated mycosis represented bymycotic meningitis, mycotic infectious disease of respiratory organ,fungemia, mycosis of urinary tract or the like. Of these, deep seatedmycosis such as candidiasis or aspergillosis tends to show a markedincrease in recent days owing to the frequent use of an anticancerchemotherapeutic agent or immunosuppressive agent or lowering in thebioimmunology due to HIV infection or the like. There is accordingly ademand for a pharmaceutical efficacious against fungi causing suchdiseases.

As pharmaceuticals effective against Aspergillus spp. and Candida spp.,Amphotericin B and azole base compounds such as Fluconazole andItraconazole are conventionally known, but not so many pharmaceuticalshave been commercially available yet. In addition, the above-exemplifiedpharmaceuticals involve problems in safety and antimycotic action. Thereis accordingly a demand for an antimycotic effective against Aspergillusspp. and Candida spp. Now, more effective azole base compounds are underdevelopment. For example, as a compound having a difluoromethylenegroup, those described in Japanese Patent Application Laid-Open Nos.163374/1984, 163269/1993 and 227531/1996 are known. As an azole basecompound having a tertiary hydroxyl group, cyclic compounds as describedin Japanese Patent Application Laid-Open Nos. 217778/1996 and333367/1996, acyl compounds as described in Japanese Patent ApplicationLaid-Open Nos. 104676/1996 and 183769/1997, and the like are known butthey are not fully satisfactory.

SUMMARY OF THE INVENTION

Accordingly, an object of the present invention is to provide a compoundwhich has high safety and has antimycotic activity effective againstAspergillus spp. and Candida spp.

With the forgoing in view, the present inventors synthesized a number oftriazole derivatives and salts thereof and carried out an investigationon their antimycotic activity effective against Aspergillus spp. andCandida spp. As a result, it has been found that an ethylthio- orethylsulfonyl-containing triazole derivative represented by thebelow-described formula (1) and a salt thereof are superior inantimycotic activity against fungi including Aspergillus spp. andCandida spp. and also in safety to the analogous compounds which havebeen known to date, leading to the completion of the present invention.

In one aspect of the present invention, there is thus provided atriazole derivative represented by the following formula (1):

wherein R¹ represents a hydrogen atom, lower alkyl group or aralkylgroup, X¹ and X² are the same or different and each independentlyrepresents a hydrogen atom, a halogen atom or a halogenoalkyl group, nstands for an integer of 0 to 2, or salt thereof; an intermediate forpreparing said compound; and a preparation process of these compounds.

In another aspect of the present invention, there is also provided apharmaceutical comprising the triazole derivative (1) or salt thereof asan effective ingredient.

In a further aspect of the present invention, there is also provided apharmaceutical composition comprising the triazole derivative (1) orsalt thereof and a pharmacologically acceptable carrier.

In a still further aspect of the present invention, there is alsoprovided the use of the triazole derivative (1) or salt thereof as apharmaceutical.

In a still further aspect of the present invention, there is alsoprovided a treating method of mycotic infections, which comprisesadministering to a patient the triazole derivative (1) or salt thereof.

The triazole derivative or salt thereof according to the presentinvention has strong antimycotic activity, and an antimycotic comprisingsuch compound as an effective ingredient is useful for the preventionand treatment of mycotic infections of mammary animals including human.

BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the triazole derivative of the present invention, examples of thelower alkyl group represented by R¹ in the formula (1) include linear orbranched Cl alkyl groups. Specific examples include methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyli-pentyl and n-hexyl. As the aralkyl group represented by R¹, C₇₋₁₀aralkyl groups are preferred, with phenyl-C₁₋₄ alkyl groups being morepreferred. Specific examples include benzyl and phenetyl andphenylpropyl. As R¹, methyl and benzyl groups are preferred. Examples ofthe halogen atom represented by X¹ or X² include fluorine, chlorine,bromine and iodine atoms, with the fluorine and chlorine atoms beingparticularly preferred. Examples of the halogenoalkyl group include theabove-exemplified C₁₋₆ alkyl groups substituted by the above-exemplifiedhalogen atom. Among them, a perfluoroalkyl group is preferred, withtrifluoromethyl and pentafluoroethyl groups being particularly preferredand trifluoromethyl group being more preferred. The number n of oxygenatoms stands for an integer of 0 to 2, with 0 and 2 being preferred.

No particular limitation is imposed on the salt of the triazolederivative (1) of the present invention insofar as it is apharmacologically acceptable salt. Examples include acid addition saltssuch as hydrochlorides, nitrates, hydrobromides, p-toluenesulfonates,methanesulfonates, fumarates, succinates and lactates.

The triazole derivative (1) or salt thereof according to the presentinvention has stereoisomers based on its asymmetric carbon andsulfoxide. The present invention therefore embraces any of such isomersand isomer mixtures such as racemic modifications. The triazolederivative (1) or salt thereof may exist in the form of a solvatetypified by a hydrate. The present invention also embraces solvates ofthese compounds.

The triazole derivative (1) of the present invention can be prepared,for example, in accordance with the reaction scheme described below:

wherein R¹, X¹ and X² have the same meanings as defined above and X³represents a halogen atom.

Described specifically, Compound (1a), that is, a compound of theformula (1) wherein n stands for 0 can be prepared by introducing anethylthio group into a 2-halo-acetophenone derivative (5) which is aknown compound, difluorinating the resulting ethylthio compound (4) intoCompound (2) and directly introducing a triazole methyl group intoCompound (2) or first introducing an epoxymethylene group into Compound(2) to obtain Compound (3) and then introducing a triazole group intoCompound (3). The R¹ of the resulting Compound (1a) can be alkylated oraralkylated as desired. By the oxidation of Compound (1a), Compound(1b), that is, a compound of the formula (1) wherein n stands for 1 orCompound (1c), that is, a compound of the formula (1) wherein n standsfor 2 can be prepared. Alternatively, Compound (1c) can be prepared bythe oxidation of Compound (1b).

In the above preparation process, a 2,2-difluoro-2-ethylthioacetophenonederivative represented by the formula (2) and an oxirane derivativerepresented by the formula (3) are novel compounds synthesized by thepresent inventors and are useful as an intermediate for the synthesis ofa triazole derivative (1).

The present invention will next be described more specifically inaccordance with the above steps.

Step (5-4)

Compound (4) can be prepared by introducing an ethylthio group intoCompound (5).

In Compound (5) employed as a starting material, examples of X³ in theformula (5) include fluorine, chlorine and bromine atoms. Among them,chlorine and bromine atoms are preferred. Compound (5) which contains asX³ a fluorine, chlorine or bromine atom and as X¹ and X² a fluorine atomare, for example, commercially available from Aldrich Chemical Co., Inc.

Compound (4) can be preparedbyreacting Compound (5) with ethyl mercaptanin the presence of a base. Examples of the reaction solvent includealcoholic solvents such as methanol and ethanol, N,N-dimethylformamide,1,4-dioxane and tetrahydrofuran, with the alcoholic solvents,particularly, methanol being preferred. As a base, sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, sodiumhydride, potassiumhydride, sodium methoxide, sodiumethoxide, pyridine,triethylamine or the like is usable. Among them, potassium carbonate ispreferred.

Step (4-2)

Compound (2) can be prepared by reacting Compound (4) with afluorinating reagent in a solvent.

Examples of the fluorinating agent include fluorine gas, perchlorylfluoride, potassium fluoride, spray-dried potassium fluoride,freeze-dried potassium fluoride, tetraalkylammonium fluoride,tris(dimethylamino)sulfa(trimethylsilyl)difluoride, N-fluoropyridone,N-fluoro-N-alkyl-arenesulfonamide, N-fluoroquinuclidinium salt,N-fluoroperfluoroalkyl sulfonimide, N-fluorosaltum, fluorinated xenon,N-fluoropyridinium salt and N-fluoropyridinium sulfonate. Examples ofthe commercially available fluorinating reagent include “OnodaFluorinates FP-T300, FP-T500, FP-T700, FP-B300, FP-B500, FP-B700 andFP-B800” (trade names; products of Chichibu Onoda Co., Ltd.) and“MEC-01, MEC-02, MEC-03, MEC-04 and MEC-05” (trade names; products ofDaikin Industries, Ltd.). It is preferred to use the fluorinatingreagent in an amount of 2 to 20 equivalents per mole of Compound (4).

Illustrative of the reaction solvent include 1,2-dichloroethane,1,1,2-trichloroethane, chloroform, methylene chloride, diethyl ether,ethyl acetate and tetrahydrofuran. Among them, 1,1,2-trichloroethane ispreferred. The reaction temperature is −78° C. to the boiling point of asolvent, with 80 to 100° C. being preferred.

To improve the yield of the compound, a Lewis acid or a base can beused. Exemplary Lewis acids include aluminum chloride, zinc chloride andtin chloride, while exemplary bases include sodium hydroxide, potassiumhydroxide, barium hydroxide, sodium carbonate, potassium carbonate,sodium hydride, potassium tert-butoxide, lithium diisopropylamide andpotassium hexamethyldisilazane.

Step (2-1a):

Direct synthesis from Compound (2) to Compound (1a) is carried out byreacting 1 mole of Compound (2) with 1 to 5 moles of anepoxymethylene-introducing agent and 1 to 4 moles of 1,2, 4-triazole oralkaline metal salt thereof at −100° C. to room temperature or boilingpoint of the solvent for 1 to 30 hours in a solvent. Examples of theepoxymethylene-introducing agent include trimethylsulfoxonium iodide andtrimethyl-sulfonium iodide. Examples of the base include sodiumhydroxide, potassium hydroxide, barium hydroxide, sodium methoxide,sodium carbonate, potassium carbonate and sodium hydride, with potassiumhydroxide being particularly preferred. As the solvent, methanol,ethanol, isopropanol, n-butanol, sec-butanol, t-butanol and the like arepreferred.

Step (2-3)

Compound (1a) can be prepared via Compound (3).

Compound (3) can be obtained by reacting Compound (2) with 1 to 2equivalents of an epoxymethylene-introducing agent such astrimethylsulfoxonium iodide or trimethylsulfonium iodide in the presenceof 1 to 5 equivalents of an alkali. Dimethylsulfoxide, tetrahydrofuranor the like can be suitably used as a solvent. Examples of the baseinclude sodium hydroxide, potassium hydroxide, barium hydroxide, sodiummethoxide, sodium ethoxide, sodium carbonate, potassium carbonate andsodium hydride, with sodium hydride and sodium methoxide beingparticularly preferred. The reaction temperature preferably ranges from−100° C. to the boiling point of the solvent, with a range of from −40to 50° C. being particularly preferred.

Step (3-1a)

Compound (1a) containing as R¹ a hydrogen atom can be prepared byreacting Compound (3) with 1,2,4-triazole or alkali metal salt thereofin a solvent in the presence of a base. Preferred examples of thesolvent include N,N-dimethylformamide, acetonitrile,N,N-dimethylacetamide and dimethylsulfoxide. Examples of the baseinclude sodium hydroxide, potassium hydroxide, barium hydroxide, sodiumcarbonate, potassium carbonate and tert-butoxy potassium. The reactiontemperature preferably ranges from 0° C. to the boiling point of thesolvent, with a range of 20 to 60° C. being particularly preferred.

Compound (1a) containing as R¹ a hydrogen atom can be converted intothat containing as R¹ a lower alkyl or aralkyl group by alkylating oraralkylating the tertiary hydroxyl group in the presence of a base asdesired. Examples of the alkyl halide to be used for the alkylationinclude methyl iodide, ethyl iodide, propyl iodide and benzyl chloride.Examples of the base include sodium hydroxide, potassium hydroxide,barium hydroxide, sodium carbonate, potassium carbonate and sodiumhydride. Examples of the solvent include alcoholic solvents such asmethanol and ethanol, nonaqueous polar solvents such asN,N-dimethylformamide (DMF) and ether solvents such as 2,4-dioxane andtetrahydrofuran (THF), with DMF being particularly preferred. Thereaction temperature preferably ranges from −40° C. to the boiling pointof the solvent, with 0 to 20° C. being particularly preferred.

Step (1a-1c)

Compound (1c) can be prepared by adding at least 2 equivalents,preferably 2.2 to 2.3 equivalents of an oxidizing agent to Compound(1a). Examples of the oxidizing agent include m-chloroperbenzoic acid,aqueous hydrogen peroxide, peracetic acid, tetrapropylammoniumperruthenate, osmium tetraoxide, potassium permanganate and oxone.Illustrative of the solvent include chloroform, dichloromethane, aceticacid, methanol, water, acetonitrile and carbon tetrachloride, andmixtures thereof. The reaction temperature is preferably −40° C. to theboiling point of the solvent, with 0 to 50° C. being particularlypreferred. To improve the yield, ruthenium trichloride, seleniumdioxide, sodium tungstate, sodium molybdate and vanadium oxide may beused as a catalyst.

Step (1a-1b) and Step (1b-1c)

Compound (1b) can be prepared by adding 1 to 2 equivalents, preferably1.2 equivalents of an oxidizing agent to Compound (1a). Examples of theoxidizing agent include m-chloroperbenzoic acid, aqueous hydrogenperoxide, peracetic acid, tetrapropylammonium perruthenate, osmiumtetraoxide, potassium permanganate and oxone. Illustrative of thesolvent include chloroform, dichloromethane, acetic acid, methanol,water, acetonitrile and carbon tetrachloride, and mixtures thereof. Thereaction temperature is preferably −40° C. to the boiling point of thesolvent, with 0 to 50° C. being particularly preferred. To improve theyield, ruthenium trichloride, selenium dioxide, sodium tungstate, sodiummolybdate and vanadium oxide may be used as a catalyst. Step (1b-1c) canbe carried out similarly.

Compounds (1a), (1b) and (1c) each has enantiomers based on itsasymmetric carbon atom. Such an optically active substance can beprepared by separating using a column for separation of an opticalisomer. Examples of the optically active stationary phase includesynthetic optically active polymers, natural high molecules and aminoacid metal complexes. Among them, a cellulose-derivative-coated silicagel is preferred. As a column filled with thiscellulose-derivative-coated silica gel, commercially-available productssuch as CHIRALCEL OD and CHIRALPAK AS (each, trade name; product ofDaicel Chemical Industries, Ltd.) can be used, with CHIRALCEL OD beingparticularly preferred. As chromatography, liquid chromatography ispreferred. In this case, hexane-ethanol, hexane-isopropyl alcohol can beused as an eluent as a mobile phase.

The optically active substance can also be prepared by opticalresolution. Examples of the reagent for optical resolution includeoptically active camphor-sulfonic acid or salt thereof which may besubstituted with a halogen atom. Specific examples include(+)-camphor-10-sulfonic acid, (−)-camphor-10-sulfonic acid,(+)-3-bromocamphor-8-sulfonic acid, (−)-3-bromocamphor-8-sulfonic acid,(+)-3-bromocamphor-10-sulfonic acid, (−)-3-bromocamphor-10-sulfonicacid, ammonium (+)-3-bromocamphor-8-sulfonate and ammonium(−)-3-bromocamphor-7-sulfonate. Among them,(+)-3-bromocamphor-8-sulfonic acid, (−)-3-bromocamphor-8-sulfonic acid,ammonium (+)-3-bromocamphor-8-sulfonate and ammonium(−)-3-bromocamphor-7-sulfonate are particularly preferred.

No particular limitation is imposed on the isolation means of a targetproduct from the reaction mixture available by each of theabove-described reactions. The target product can be isolated, forexample, by recrystallization, various types of chromatography or thelike. Moreover, the target compound can be converted into a desired saltin a conventional manner.

From the invention compound, a pharmaceutical, particularly, anantimycotic can be obtained in various dosage forms such as tablets,granules, powders, capsules, suspensions, injections, suppositories andexternal preparations. In this case, it is possible to prepare thepharmaceutical by incorporating therein a pharmacologically acceptablecarrier. Described specifically, a solid preparation can be prepared ina conventional manner by adding to the invention compound (1) anexcipient and, if necessary, a binder, disintegrator, extender, coatingagent, sugar-coating agent and/or the like. An injection may be preparedby dissolving, dispersing or emulsifying the invention compound (1) inan aqueous carrier such as distilled water for injection to form aninjection liquid in advance or to prepare powder for injection anddissolve it upon use. Examples of the administration method of theinjection include intravenous administration, intraarterialadministration, intraperitoneal administration, subcutaneousadministration and instillation.

The dose of the invention compound or salt thereof as a pharmaceuticaldiffers depending on various factors such as symptoms, weight, age orsex of the patient to be administered or administration route. When usedas an antimycotic, the pharmaceutical is used in an amount of 0.1 to1000 mg/day, preferably 1 to 300 mg/day per adult in terms of theinvention compound (1) or salt thereof. It is possible to add theabove-described amount once a day or 2 to 4 portions a day.

EXAMPLES

The present invention will hereinafter be described in detail byreferential examples and examples. It should however be borne in mindthat the present invention will not be limited to or by the followingexamples.

Referential Example 1 Synthesis of2′,4′-difluoro-2-(ethylthio)acetophenone [Compound (4-1)]

To a solution of 2-chloro-2′,4′-difluoroacetophenone (10 g, 0.053 mol)and ethyl mercaptan (3.6 g, 0.058 mol) in methanol (200 ml), potassiumcarbonate (8.8 g, 0.064 mol) was added under ice cooling, followed bystirring at room temperature for 1.5 hours. After the completion of thereaction, the solvent was distilled off under reduced pressure. Waterwas added to the residue, followed by extraction with ether. The extractwas washed successively with water and saturated saline and dried overmagnesium sulfate. The solvent was then distilled off under reducedpressure. The resulting oil was distilled under reduced pressure (bp:115 to 118° C., 2 mmHg), whereby2′,4′-difluoro-2-(ethylthio)acetophenone (11.4 g, yield: 99.9%) wasobtained as a colorless oil.

¹H-NMR(CDCl₃, δ): 1.24(3H,t,J=7 Hz), 2.51(2H,q,J=7 Hz), 3.77(2H,d,J=2Hz), 6.75-7.09(2H,m), 7.86-8.13(1H,m).

Referential Example 2 Synthesis of 2-ethylthio-4′-fluoroacetophenone[Compound (4-2)]

In a similar manner to Referential Example 1 except for the use of2-chloro-4′-fluoroacetophenone instead of2-chloro-2′,4′-difluoroacetophenone, 2-ethylthio-4′-fluoroacetophenonewas obtained as a colorless oil.

¹H-NMR(CDCl₃, δ): 1.27(3H,t,J=7.2 Hz), 2.58(2H,q,J=7.2 Hz), 3.77(2H,s),7.00-7.40(2H,m), 7.90-8.10(2H,m).

Referential Example 3 Synthesis of2-ethylthio-4′-trifluoromethylacetophenone [Compound (4-3)]

In a similar manner to Referential Example 1 except for the use of2-bromo-4′-trifluoromethylacetophenone instead of2-chloro-2′,4′-difluoroacetophenone,2-ethylthio-4′-trifluoromethylacetophenone was obtained as a colorlessoil.

¹H-NMR(CDCl₃, δ): 1.27(3H,t,J=7.5 Hz), 2.57(2H,q,J=7.5 Hz), 3.80(2H,s),7.74(2H,d,J=8.4 Hz), 8.10(2H,d,J=8.4 Hz).

Referential Example 4 Synthesis of2′,4′-dichloro-2-(ethylthio)acetophenone [Compound (4-4)]

In a similar manner to Referential Example 1 except for the use of2,2′,4′-trichloroacetophenone instead of2-chloro-2′,4′-difluoroacetophenone,2′,4′-dichloro-2-(ethylthio)acetophenone was obtained as a colorlessoil.

¹H-NMR(CDCl₃, δ): 1.25(3H,t,J=7.3 Hz), 2.55(2H,q,J=7.3 Hz), 3.80(2H,s),7.20-7.70(3H,m).

Example 1 Synthesis of 2-ethylthio-2,2,2′,4′-tetrafluoroacetophenone[Compound (2-1)

To a solution of 2′,4′-difluoro-2-(ethylthio)acetophenone (11.4 g, 0.053mol) in 1,1,2-trichloroethane (100 ml),N-fluoro-4-methylpyridinium-2-sulfonate (“MEC-02”, trade name; DaikinKogyo Co., Ltd.) (24 g, 0.127 mol) was added in portions at an internaltemperature of 90° C., followed by stirring at an internal temperatureof 95 to 100° C. for 1.5 hours. After the completion of the reaction,the internal temperature was cooled to 50° C. or lower. Water was addedto the reaction mixture, followed by extraction with1,1,2-trichloroethane. The extract was washed successively with waterand saturated saline and dried over magnesium sulfate. The solvent wasthen distilled off under reduced pressure. The resulting oil wasdistilled under reduced pressure (bp: 105 to 110° C., 3 mmHg), whereby2-ethylthio-2,2,2′,4′-tetrafluoroacetophenone (4.6 g, yield: 35%,) wasobtained as a colorless oil.

¹H-NMR(CDCl₃, δ): 1.37(3H,t,J=7 Hz), 2.92(2H,q,J=7 Hz), 6.81-7.12(2H,m),7.85-8.11 (1H,m).

Example 2 Synthesis of 2-ethylthio-2,2,4′-trifluoroacetophenone[Compound (2-2)]

In a similar manner to Example 1 except for the use of2-ethylthio-4′-fluoroacetophenone instead of2-ethylthio-2′,4′-difluoroacetophenone,2-ethylthio-2,2,4′-trifluoroacetophenone was obtained as a colorlessoil.

¹H-NMR(CDCl₃, δ): 1.38(3H,t,J=7.5 Hz), 2.93(2H,q,J=7.5 Hz),7.76(2H,d,J=8.6 Hz), 8.24(2H,d,J=8.6 Hz).

Example 3 Synthesis of2-ethylthio-2,2-difluoro-4′-(trifluoromethyl)acetophenone [Compound(2-3)]

In a similar manner to Example 1 except for the use of2-ethylthio-4′-trifluoromethylacetophenone instead of2-ethylthio-2′,4′-difluoroacetophenone,2-ethylthio-2,2-difluoro-4′-(trifluoromethyl)acetophenone was obtainedas a colorless oil.

¹H-NMR(CDCl₃, δ): 1.38(3H,t,J=7.5 Hz), 2.94(2H,q,J=7.5 Hz),7.00-7.40(2H,m), 8.0-8.4(2H,m).

Example 4 Synthesis of2′,4′-dichloro-2-ethylthio-2,2-difluoroacetophenone [Compound (2-4)]

In a similar manner to Example 1 except for the use of2′,4′-dichloro-2-(ethylthio)acetophenone instead of2-ethylthio-2′,4′-difluoroacetophenone,2′,4′-dichloro-2-ethylthio-2,2-difluoroacetophenone was obtained as acolorless oil.

¹H-NMR(CDCl₃, δ): 1.37(3H,t,J=7.7 Hz), 2.90(2H,q,J=7.7 Hz),6.81-7.12(2H,m), 7.20-7.80(2H,m).

Example 5 Synthesis of2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane [Compound(3-1)]

A suspension of 60%) NaH (876 mg, 0.022 mol) in THF (30 ml)-DMSO (50 ml)was heated to an external temperature of 50° C., followed by theaddition of trimethylsulfoxonium iodide (4.8 g, 0.022 mol) in portions.After stirring at the same temperature for one hour, the reactionmixture was cooled to −20° C. and added dropwise with a solution of2-ethylthio-2,2,2′,4′-tetrafluoroacetophenone (4.6 g, 0.018 mol) in THF(20 ml). The resulting mixture was stirred at room temperature for 2hours. The reaction mixture was then poured into ice water, followed byextraction with ethyl acetate. The extract was washed successively withwater and saturated saline and dried over magnesium sulfate. The solventwas then distilled off under reduced pressure, whereby2-(2,4-difluorophenyl)-2-[(ethylthio) (difluoro)methyl]oxirane (4.3 g,yield: 90.0%) was obtained as a pale yellow oil.

¹H-NMR(CDCl₃, δ): 1.30(3H,t,J=7 Hz), 2.86(2H,q,J=7 Hz), 2.95-2.98(1H,m),3.48(1H,d,J=5Hz), 6.71-7.02(2H,m), 7.40-7.66(1H,m).

Example 6 Synthesis of2-[(ethylthio)(difluoro)methyl]-2-(4-fluorophenyl)oxirane [Compound(3-2)]

In a similar manner to Example 5 except for the use of2-ethylthio-2,2,4′-trifluoroacetophenone instead of2-ethylthio-2,2,2′,4′-tetrafluoroacetophenone,2-[(ethylthio)(difluoro)methyl]-2-(4-fluorophenyl)oxirane was obtainedas a pale yellow oil.

¹H-NMR(CDCl₃, δ): 1.30(3H,t,J=7.5 Hz), 2.86(3H,m), 3.46(1H,d,J=5.5 Hz),6.80-7.30(2H,m), 7.40-7.70(2H,m).

Example 7 Synthesis of2-[(ethylthio)(difluoro)methyl]-2-(4-trifluoromethylphenyl)oxirane[Compound (3-3)]

In a similar manner to Example 5 except for the use of2-ethylthio-2,2-difluoro-4′-(trifluoromethyl)acetophenone instead of2-ethylthio-2,2,2′,4′-tetrafluoroacetophenone,2-[(ethylthio)(difluoro)methyl]-2-(4-trifluoromethylphenyl)oxirane wasobtained as a pale yellow oil.

¹H-NMR(CDCl₃, δ): 1.31(3H,t,J=7.5 Hz), 2.60-3.00(3H,m), 3.50(1H,d,J=5.5Hz), 6.80-7.30(2H,m), 7.66(4H,br.s).

Example 8 Synthesis of2-(2,4-dichlorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane [Compound(3-4)]

In a similar manner to Example 5 except for the use of2-ethylthio-2′,4′-dichloro-2,2-difluoroacetophenone instead of2-ethylthio-2,2,2′,4′-tetrafluoroacetophenone,2-(2,4-dichlorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane wasobtained as a pale yellow oil.

¹H-NMR(CDCl₃, δ): 1.30(3H,t,J=7.5 Hz), 2.60-3.10(3H,m), 3.58(1H,d,J=5.1Hz), 6.80-7.30(2H,m), 7.20-7.60(3H,m).

Example 9 Synthesis of2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1a-1)]

To a solution of2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane (4.3 g,0.016 mol) in DMSO (50 ml), 1,2,4-triazole (2.98 g, 0.043 mol) andpotassium carbonate (5.96 g, 0.043 mol) were added, followed by stirringat 60° C. for 2 hours. After the completion of the reaction, water wasadded to the reaction mixture. The resulting mixture was extracted withethyl acetate. The extract was washed successively with water andsaturated saline and dried over magnesium sulfate. The solvent was thendistilled off under reduced pressure. The residue so obtained wascrystallized from isopropyl ether-ethyl acetate, whereby2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(1.5 g, yield: 25%) was obtained as colorless crystals.

Melting point: 109 to 110° C.

IR(KBr) v_(max)cm⁻¹: 3136, 1681, 1499, 1145

MS(FAB): 336(M+H)

¹H-NMR(CDCl₃, δ); 1.29(3H,t,J=7 Hz), 2.84(2H,q,J=7 Hz), 4.79(1H,d,J=14Hz), 5.28(1H,d,J=14 Hz), 5.74(1H,s), 6.60-6.95(2H,m), 7.60-7.87(1H,m),7.79(1H,s), 8.09(1H,s).

Example 10 Synthesis of1-(ethylthio)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1a-2)]

In a similar manner to Example 9 except for the use of2-[(ethylthio)(difluoro)methyl]-2-(4-fluorophenyl)oxirane instead of2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane,1-(ethylthio)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 101 to 102° C.

IR(KBr) v_(max)cm⁻¹: 3111, 1584, 1519, 1144

MS(FAB): 318(M+H)

¹H-NMR(CDCl₃, δ): 1.27(3H,t,J=7.5 Hz), 2.80(2H,q,J=7.5 Hz),4.78(1H,d,J=14.5 Hz), 4.90(1H,d,J=14.5 Hz), 5.72(1H,s), 6.85-7.10(2H,m),7.40-7.70(1H,m), 7.77(1H,s), 7.93(1H,s).

Example 11 Synthesis of1-(ethylthio)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1a-3)]

In a similar manner to Example 9 except for the use of2-[(ethylthio)(difluoro)methyl]-2-(4-trifluoromethylphenyl)oxiraneinstead of2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane,1-(ethylthio)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 122 to 123° C.

IR(KBr) v_(max)cm⁻¹: 3207, 1620, 1514, 1121

MS (FAB): 368 (M+H)

¹H-NMR(CDCl₃, δ): 1.27(3H,t,J=7.5 Hz), 2.81(2H,q,J=7.5 Hz),4.72(1H,d,J=14.5 Hz), 4.95(1H,d,J=14.5 Hz), 5.41(1H,s), 7.58(2H,d,J=9.2Hz), 7.70(2H,d,J=9.2 Hz), 7.87(1H,s), 7.95(1H,s).

Example 12 Synthesis of2-(2,4-dichlorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1a-4)]

In a similar manner to Example 9 except for the use of2-(2,4-dichlorophenyl)-2-[(ethylthio)(difluoro)methyl]-oxirane insteadof 2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane,2-(2,4-dichlorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 98 to 100° C.

IR(KBr) v_(max)cm⁻¹: 3112, 1614, 1519, 1108

MS (FAB): 368 (M+H)

¹H-NMR(CDCl₃, δ): 1.30(3H,t,J=7.5 Hz), 2.85(2H,q,J=7.5 Hz),4.85(1H,d,J=14.3 Hz), 5.82(1H,d,J=14.5 Hz), 5.91(1H,s), 7.05-7.30(2H,m),7.82(1H,s), 7.89(1H,d,J=8.6 Hz), 8.20(1H,s).

Example 13 Synthesis of1-[2-(2,4-difluorophenyl)-3-ethylthio-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole[Compound (1a-5)]

To a solution of 60% sodium hydride (0.16 g, 4.0 mmol) inN,N-dimethylformamide (50 ml),2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazole-1-yl)-2-propanol(1.0 g, 3.0 mmol) was added dropwise under ice cooling, followed bystirring at room temperature for 30 minutes. Methyl iodide (0.56 g, 3.9mmol) was then added dropwise to the reaction mixture under ice coolingand the resulting mixture was stirred at room temperature for 1 hour.Water was added to the reaction mixture, followed by extraction withether. The ether solution was washed with water and dried over sodiumsulfate. The solvent was then distilled off under reduced pressure. Theresidue was subjected to a silica gel column and from the chloroformeluate fraction,1-[2-(2,4-difluorophenyl)-3-ethylthio-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole(0.81 g, yield: 78%) was obtained as a colorless oil.

MS(FAB): 350(M+H)

¹H-NMR(CDCl₃, δ): 1.29(3H,t,J=7.5 Hz), 2.82(2H,q,J=7.5 Hz),3.70-3.74(3H,m), 5.10(2H,br.s), 6.6-6.9(1H,m), 7.4-7.7(1H,m),7.80(1H,s), 8.00(1H,s).

Example 14 Synthesis of1-[2-(benzyloxy)-2-(2,4-difluorophenyl)-3-(ethylthio)-3,3-difluoropropyl]-1H-1,2,4-triazole[Compound (1a-6)]

In a similar manner to Example 13 except for the use of benzyl chlorideinstead of methyl iodide,1-[2-(benzyloxy)-2-(2,4-difluorophenyl)-3-(ethylthio)-3,3-difluoropropyl]-1H-1,2,4-triazolewas obtained as a colorless oil.

MS(FAB): 426(M+H)

¹H-NMR(CDCl₃, δ): 1.31(3H,t,J=7.3 Hz), 2.85(2H,q,J=7.3 Hz),4.8-5.3(4H,m), 6.6-6.9(2H,m), 7.2-7.6(6H,m), 7.78(1H,s), 7.94(1H,s).

Example 15 Synthesis of2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazole-1-yl)-2-propanol[Compound (1c-1)]

To a solution of2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(850 mg, 2.39 mmol) in dichloromethane (100 ml), 85% m-chloroperbenzoicacid (1.4 g, 5.75 mmol) was added at room temperature, followed bystirring at room temperature for 12 hours. After the completion of thereaction, a saturated aqueous solution of sodium thiosulfate and asaturated aqueous solution of sodium bicarbonate were added and theresulting mixture was stirred. The dichloromethane solution wasseparated and after washing with water, dried over magnesium sulfate.The solvent was then distilled off under reduced pressure. The residueso obtained was crystallized from isopropyl ether-ethyl acetate, whereby2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(718 mg, yield: 78%) was obtained as colorless crystals.

Melting point: 117 to 118° C.

IR(KBr) v_(max)cm⁻¹: 3136, 1617, 1503, 1323

MS (FAB): 368 (M+H)

¹H-NMR(CDCl₃, δ): 1.48(3H,t,J=7 Hz), 3.41(2H,q,J=7 Hz), 5.14(1H,d,J=14Hz), 5.37(1H,d,J=14 Hz), 6.11(1H,s), 6.64-6.96(2H,m), 7.55-7.82(1H,m),7.77(1H,s), 8.07(1H,s).

Example 16 Synthesis of1-(ethylsulfonyl)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-2)]

In a similar manner to Example 15 except for the use of1-(ethylthio)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolinstead of2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,1-(ethylsulfonyl)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 82 to 84° C.

IR(KBr) v_(max)cm⁻¹: 3110, 1587, 1518, 1332

MS(FAB): 350(M+H)

¹H-NMR(CDCl₃, δ): 1.46(3H,t,J=7.5 Hz), 3.35(2H,q,J=7.5 Hz),4.83(1H,d,J=14.5 Hz), 5.27(1H,d,J=14.5 Hz), 5.81(1H,br.s),6.90-7.10(2H,m), 7.30-7.60(2H,m), 7.80(1H,s), 7.90(1H,s).

Example 17 Synthesis of1-(ethylsulfonyl)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-3)]

In a similar manner to Example 15 except for the use of1-(ethylthio)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolinstead of2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,1-(ethylsulfonyl)-1,1-difluoro-2-(4-trifluoromethylphenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 155 to 157° C.

IR(KBr) v_(max)cm⁻¹: 3207, 1620, 1514, 1329

MS(FAB): 400(M+H)

¹H-NMR(CDCl₃, δ): 1.47(3H,t,J=7.5 Hz), 3.38(2H,q,J=7.5 Hz),4.88(1H,d,J=14.3 Hz), 5.32(1H,d,J=14.3 Hz), 6.09(1H,br.s), 7.64(4H,s),7.78(1H,s), 7.92(1H,s).

Example 18 Synthesis of2-(2,4-dichlorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-4)]

In a similar manner to Example 15 except for the use of2-(2,4-dichlorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanolinstead of2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,2-(2,4-dichlorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanolwas obtained as colorless crystals.

Melting point: 79 to 81° C.

IR(KBr) v_(max)cm⁻¹: 3421, 1617, 1518, 1331

MS(FAB): 400(M+H)

¹H-NMR(CDCl₃, δ): 1.50(3H,t,J=7.7 Hz), 3.43(2H,q,J=7.7 Hz),5.20(1H,d,J=14.7 Hz), 6.13(1H,d,J=14.7 Hz), 6.31(1H,br.s),7.10-7.40(2H,m), 7.88(1H,s), 7.74(1H,d,J=8.1 Hz), 8.16(1H,s).

Example 19 Synthesis of1-[2-(2,4-difluorophenyl)-3-ethylsulfonyl-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole[Compound (1c-5)]

In a similar manner to Example 15 except for the use of1-[2-(2,4-difluorophenyl)-3-ethylthio-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazoleinstead of2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,1-[2-(2,4-difluorophenyl)-3-ethylsulfonyl-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazolewas obtained as a colorless oil.

MS (FAB): 382 (M+H)

¹H-NMR(CDCl₃, δ): 1.43(3H,t,J=7.5 Hz), 3.20(2H,q,J=7.5 Hz),3.75(3H,br.s), 5.15(1H,d,J=5.5 Hz), 5.24(1H,d,J=5.5 Hz), 6.6-7.0(2H,m),7.4-7.7(1H,m), 7.78(1H,s), 8.06(1H,s).

Example 20 Synthesis of1-[2-(benzyloxy)-2-(2,4-difluorophenyl)-3-(ethylsulfonyl)-3,3-difluoropropyl]-1H-1,2,4-triazole[Compound (1c-6)]

In a similar manner to Example 15 except for the use of1-[2-(benzyloxy)-2-(2,4-difluorophenyl)-3-(ethylthio)-3,3-difluoropropyl]-1H-1,2,4-triazoleinstead of2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol,1-[2-(benzyloxy)-2-(2,4-difluorophenyl)-3-(ethylsulfonyl)-3,3-difluoropropyl]-1H-1,2,4-triazolewas obtained as a colorless oil.

(FAB): 458(M+H)

¹H-NMR(CDCl₃, δ): 1.41(3H,t,J=7.3 Hz), 3.19(2H,q,J=7.3 Hz), 5.07(2H,s),5.27(1H,d,J=15.8 Hz), 5.50(1H,d,J=15.8 Hz), 6.6-7.0(2H,m),7.2-7.7(6H,m), 7.80(1H,s), 8.03(1H,s).

Example 21 Optical resolution of2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-1)] by using a column for the separation of an opticallyactive substance.

(±)-2-(2,4-Difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(40 mg) was subjected to CHIRALCEL OD (trade name; product of DaicelChemical Industries, Ltd.), that is, a column for the separation of anoptically active substance. From the eluate fraction of a 4:1hexane-isopropyl alcohol mixture, 17 mg (optical purity: 100% e.e.) of(+) form as colorless crystals and 17 mg (optical purity: 100% e.e.) of(−) form as colorless crystals were obtained in the order of elution.

(1)(+)-2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H,1,2,4-triazol-1-yl)-2-propanol

[α]_(D) ^(21.7)+21.0° (C=0.1, acetone)

Melting point: 120 to 121° C.

IR(KBr) v_(max)cm⁻¹: 3136, 1617, 1503, 1323

MS(FAB): 368(M+H)

¹H-NMR(CDCl₃, δ): 1.48(3H,t,J=7 Hz), 3.41(2H,q,J=7 Hz), 5.14(1H,d,J=14Hz), 5.37(1H,d,J=14 Hz), 6.11(1H,s), 6.64-6.96(2H,m), 7.55-7.82(1H,m),7.77(1H,s), 8.07(1H,s).

(2)(−)-2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol

[α]_(D) ^(21.7) −21.5° (C=0.1, acetone)

Melting point: 120 to 121° C.

IR(KBr) v_(max)cm⁻¹: 3136, 1617, 1503, 1323

MS(FAB): 368(M+H)

¹H-NMR(CDCl₃, δ): 1.48(3H,t,J=7 Hz), 3.41(2H,q,J=7 Hz), 5.14(1H,d,J=14Hz), 5.37(1H,d,J=14 Hz), 6.11(1H,s), 6.64-6.96(2H,m), 7.55-7.82(1H,m),7.77(1H,s), 8.07(1H,s).

Example 22 Optical resolution of1-(ethylsulfonyl)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-2)] by using a column for the separation of an opticallyactive substance

In a similar manner to Example 21 except for the use of(±)-2-(4-fluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol(220 mg) instead of(±)-1-(ethylsulfonyl)-1,1-difluoro-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol,100 mg (optical purity: 100% e.e.) of (+) form as colorless crystals and100 mg (optical purity: 100% e.e.) of (−) form as colorless crystalswere obtained in the order of elution.

(1)(+)-1-(Ethylsulfonyl)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol

[α]_(D) ^(20.6)+23.0° (C=0.1, acetone)

Melting point: 131 to 132° C.

IR(KBr) v_(max)cm⁻¹: 3447, 1636, 1511, 1336

MS(FAB): 350(M+H)

¹H-NMR(CDCl₃, δ): 1.46(3H,t,J=7.5 Hz), 3.35(2H,q,J=7.5 Hz),4.83(1H,d,J=14.5 Hz), 5.27(1H,d,J=14.5 Hz), 5.81(1H,br.s),6.90-7.10(2H,m), 7.30-7.60(2H,m), 7.80(1H,s), 7.90(1H,s).

(2)(−)-1-(Ethylsulfonyl)-1,1-difluoro-2-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol

[α]_(D) ^(20.6)+20.0° (C=0.1, acetone)

Melting point: 131 to 132° C.

IR(KBr) v_(max)cm⁻¹: 3447, 1636, 1511, 1336

MS (FAB): 350(M+H)

¹H-NMR(CDCl₃, δ):

1.46(3H,t,J=7.5 Hz), 3.35(2H,q,J=7.5 Hz), 4.83(1H,d,J=14.5 Hz),5.27(1H,d,J=14.5 Hz), 5.81(1H,br.s), 6.90-7.10(2H,m), 7.30-7.60(2H,m),7.80(1H,s), 7.90(1H,s).

Example 23 Preparation process of(−)-1-(ethylsulfonyl)-1,1-difluoro-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol[Compound (1c-1)] by using a reagent for optical resolution

In isopropyl alcohol (3.0 L),(±)-1-(ethylsulfonyl)-1,1-difluoro-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol(130 g) and (+)-3-bromocamphor-8-sulfonic acid (115.7 g) were dissolvedunder heating, followed by inoculation of seed crystals. The reactionmixture was allowed to stand at room temperature for 5 days. Thecrystals so precipitated were collected by filtration, whereby 135.8 g(optical purity: 56.7% e.e.) of a (+)-3-bromocamphor-8-sulfonate salt of(−)-1-(ethylsulfonyl)-1,1-difluoro-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwere obtained as colorless crystals. Recrystallization of the crystalsso obtained was repeated using isopropyl alcohol as a solvent, whereby72.1 g (optical purity: 93.1% e.e.) of a (+)-3-bromocamphor-8-sulfonatesalt of(−)-1-(ethylsulfonyl)-1,1-difluoro-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwere obtained as colorless crystals. To the resulting salt, a 5% aqueoussolution of sodium bicarbonate was added to make it alkaline, followedby extraction with ethyl acetate. The extract was washed with water anddried. The solvent was then distilled off under reduced pressure. Theresidue was recrystallized from ethyl acetate-ether, whereby 41.4 g(optical purity: 99.7% e.e.) of(−)-1-(ethylsulfonyl)-1,1-difluoro-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanolwere obtained as colorless crystals.

Test 1: Action against Candida albicans (in vitro)

To each well of a 96-well microtiter plate, 75 μl of a dilute medicamentsolution adjusted with a 10% fetal-bovine-serum added MEM medium(containing glutamine and a carbonate) were poured, followed by theaddition of 75 μl of 4×10⁴ cells/ml of C. albicans ATCC 44859 suspendedin the same medium. The resulting mixture was incubated at 37° C. for 24hours in a CO gas incubator. After incubation, a morphological change ofC. albicans was observed under an inverted microscope. The minimummedicament concentration permitting the apparent suppression of mycerialtype growth compared with that of a medicament-free control wasdesignated as a terminal point (ng/ml). Incidentally, as a medicamentfor comparison, Fluconazole and known compound A ((−)-compound (1c-1) inJapanese Patent Application Laid-Open No. HEI 9-227531) were employed.The results are shown in Table 1.

Test 2: Action against Aspergillus fumigatus (in vitro)

To each well of a 96-well microtiter plate, 100 μl of a dilutemedicament solution adjusted with 0.165M MOPS-containing RPMI 1640medium (containing glutamine and phenol red, carbonate free; pH 7) werepoured, followed by the addition of 100 μl of 6.0×10⁴ conidia/ml of anA. fumigatus IFM 40808 spore suspension in the above medium containing20% almar Blue. They were incubated at 35° C. for 48 hours. Judgment wasmade visually and the minimum medicament concentration not permitting achange into red (the medium maintained blue color) was designated as anMIC value (μg/ml). Incidentally, as a medicament for comparison,Fluconazole and known compound A ((−)-compound (1c-1) in Japanese PatentApplication Laid-Open No. HEI 9-227531) were employed. The results areshown in Table 1.

TABLE 1 Terminal point (ng/ml) MIC (μg/ml) Test compound C. albicanis A.fumigatus Example 9 7.8 2 Example 10 31.3 8 Example 11 7.8 16 Example 123.9 1 Example 13 31.3 8 Example 15 31.3 8 Example 18 15.6 8 Example 21(2) 15.6 4 Example 22 (2) 15.6 8 Fluconazole 250 >128 Known compound A62.5 16

Test 3: Action against Candida albicans (in vivo)

After 4-week-old, male, ICR (CRJ: CD-1) mice were fasted for 6 hours, C.albicans IFM 40009 was inoculated to the tail vein of each of the miceto give an amount of 3.0×10⁶ cells/mouse, whereby infection was caused.A control group consisted of 11 mice, while a medicament-administeredgroup consisted of 5 mice. The medicament dissolved in 20% polyethyleneglycol was orally administered 1 hour after the inoculation of thefungus and then consecutively once a day 24 hours after the inoculation,four times in total, at 1.25 mg/kg each. The survival condition on Day14 after the infection was compared. In addition, the survival days ofthe control group and the medicament-administered group were detected bythe Kaplan-Meier method (Cox mantel test). Incidentally, Fluconazole wasemployed as a medicament for comparison. The results are shown in Table2.

TABLE 2 Surviving mice on Day 14 Average number of surviving mice/ TestCompound Survival days total number in group Example 15 14.00*** 4/5Fluconazole 11.0*** 1/5 Control 4.5  0/11 (relative to control: ***p <0.001)

Formulation examples will next be described.

EXAMPLE 24 Tablets Compound of Example 21(2) 50 mg Crystalline cellulose50 mg Lactose 50 mg Hydroxypropyl cellulose 18 mg Magnesium stearate  2mg Total 170 mg 

In a conventional manner, tablets having the above-described compositionwere prepared. The tablets could be formed as sugar coated tablets orfilm coated tablets.

EXAMPLE 25 Capsules Compound of Example 21(2) 50 mg Light silicicanhydride 25 mg Lactose 100 mg  Starch 50 mg Talc 25 mg Total 250 mg 

The above ingredients were filled in No. 1 capsules, whereby capsuleswere obtained.

EXAMPLE 26 Granules Compound of Example 21(2)  50 mg Lactose 600 mg Cornstarch 200 mg Carboxymethyl cellulose sodium  20 mg Hydroxypropylcellulose 130 mg Total 1000 mg 

In a conventional manner, granules having the above-describedcomposition were prepared.

EXAMPLE 27 Powders Compound of Example 21(2) 50 mg Light silicicanhydride 20 mg Precipitated calcium carbonate 10 mg Lactose 250 mg Starch 70 mg Total 400 mg 

In a conventional manner, powders having the above-described compositionwere prepared.

EXAMPLE 28 Injection Compound of Example 21(2)  5 mg Hydrogenated castoroil 85 mg Propylene glycol 60 mg Glucose 50 mg Distilled water forinjection q.s. Total  1 ml

In a conventional manner, an injection having the above-describedcomposition was prepared.

EXAMPLE 29 Intravenous drip infusion Compound of Example 21(2) 50 mgHydrogenated castor oil 5 g Propylene glycol 10 mg Glucose 14.5 mgDistilled water for injection q.s. Total 100 ml

An intravenous drip infusion having the above-described composition wasprepared in a conventional manner.

Japanese Patent Application Nos. 9-359202 filed on Dec. 26, 1997 and10-186198 filed on Jul. 1, 1998, are incorporated herein by reference inits entirety.

What is claimed is:
 1. An oxirane derivative represented by thefollowing formula (3):

wherein X¹ and X² are the same or different and each independentlyrepresents a hydrogen atom, a halogen atom or a halogen(lower)alkylgroup.